Perhaps no other word or diagnosis strikes as much fear into a patient as cancer. Each year, hundreds of thousands of men, women, and children in the United States die of some form of cancer. Worldwide, millions die of cancers including those of the bone, bladder, blood (leukemias), brain, breast, colon, cervix, esophagus, intestine, kidney, liver, lung, mouth, nose, nerves, ovaries, pancreas, prostate, skin, stomach, testis, throat, thyroid, uterus, and vagina.
Over the years, a number of methods have been used to treat cancer including radiation and chemotherapy. The primary goal of these treatments is to kill all the cancer cells. However, many healthy cells are invariably destroyed in a race to kill the cancer cells before the treatment(s) kill the patient. Even today, the more measured and quantitative uses of radiation and chemotherapy can cause illness and even death in some patients. At the same time, in some types of cancer, the malignant cells remain difficult to treat. Consequently, the physiology or phenotypes of cancer cells have been extensively studied to identify new targets that can be selectively attacked to kill the cancer cells without adversely affecting the healthy cells of the patient.
It was suggested in U.S. Pat. No. 5,759,837 that fatty acid synthase (“FAS”) is overexpressed in carcinomas with a poor prognosis, but much less FAS expression is identified in normal tissues. U.S. Pat. No. 5,759,837 stated also that inhibition of fatty acid synthesis is selectively toxic to carcinoma cells, while normal cells with low FAS activity are resistant. A possible method of treating cancer patients where fatty acid synthesis by cells of the patient's tumor is inhibited with resultant interruption of the disease process is taught. Although one of the suggested inhibitors was 3-bromopyruvate (“3-BrPA”), no experiments using 3-BrPA for cancer therapy in animals was provided, and there was no mention of how it can be formulated for use in humans.
Significantly, one of the most common, profound, and intriguing phenotypes of highly malignant tumors, known for more than seven decades, is their ability to metabolize glucose at high rates in order to synthesize high levels of ATP to energize tumor growth. Under aerobic conditions more than half the ATP produced in such tumor cells may be derived via glycolysis, in sharp contrast to normal cells, where this value is usually less than 10% with oxidative phosphorylation serving as the predominant method for ATP generation. Under hypoxic (low oxygen tension) conditions, frequently present within the tumor, the already high glycolytic rate may double, allowing the tumor cells to thrive as neighboring normal cells become growth deficient. This is a characteristic of most animal and human tumors and usually occurs at an advanced poorly differentiated stage in their progression. In fact, it is known that a close correlation exists among the degrees of differentiation, growth rate, and glucose metabolism of tumors, where those that are the most poorly differentiated exhibit the fastest growth and the highest glycolytic rate. Noteworthy is the fact that this unique “high glycolytic” phenotype is used clinically worldwide in Positron Emission Tomography (“PET”) to detect tumors, assess their degree of malignancy, predict survival times, and assess the relative effectiveness of various treatments.
Despite the commonality of the high glycolytic phenotype and its widespread use clinically as a diagnostic tool, only recently has it been exploited as a major target for arresting or slowing the growth of cancer cells. This is because the underlying molecular basis of the high glycolytic phenotype, long suspected to involve some type of mitochondrial-glycolytic interaction, has only recently become understood. Thus, experiments have demonstrated a requirement for an overexpressed mitochondrially bound form of hexokinase, now identified as Type II hexokinase.
U.S. Patent Application Publication No. 20030087961 (Ko et al.) teaches that 3-BrPA is a potent energy blocker, inhibiting both ATP production sources (glycolysis and mitochondria) of tumor cells in vitro, and when delivered intra-arterially directly to a tumor site within the liver of an experimental animal (rabbit) has an impressive killing capacity in a single injection with no more than 10-16% of the tumor cells remaining alive.
A subsequent publication continued to suggest the use of a halopyruvate as a highly effective primary component in a pharmaceutical composition or treatment regimen for cancer. Specifically, Ko (Ko, Y. H. et al., Biochemical Biophysical Research Communications 324, 269-275, 2004, incorporated herein by reference) achieved complete eradication of advanced “PET Positive” hepatocellular carcinomas (“HCCs”) in a rat model using 3-BrPA therapy. Repeated injections were made of a 2 mM solution in 1×PBS (potassium phosphate buffered saline pH 7.5) directly at the tumor site. Normal tissue was unaffected as it has little propensity to take up the 3-BrPA in contrast to PET POSITIVE cancers that take up 3-BrPA and then cause cell ATP depletion followed by cell death. (PET POSITIVE tumors exhibit a positive PET scan indicating that they exhibit a rapid metabolism of glucose converting this sugar to lactic acid that is transported out of the cancer cells on specific transporters referred to here as the “lactic acid transporter.” As 3-BrPA is very structurally similar to lactate, the applicant et al. proposed that 3-BrPA likely enters cancer cells via the “lactic acid transporter”, and once inside because of its strong alkylating nature inhibits both glycolysis and mitochondrial function thus resulting in almost total cell ATP depletion and rapid cell death.)
In Ko (2004), the tumor cells had been implanted externally or in the abdominal cavity. Thus, it was possible for 3-BrPA in a freshly prepared solution (i.e., in phosphate buffered saline) to be applied directly at or near the tumor site. However, most PET POSITIVE human cancers occur in organs located internally in the body, thus emphasizing the need for a therapeutic cocktail formulated for human delivery.